Apolipoprotein A-I inhibits LPS-induced atherosclerosis in ApoE−/− mice possibly via activated STAT3-mediated upregulation of tristetraprolin
Abstract
Kai YIN1, 2, #, Shi-lin TANG1, 3, #, Xiao-hua YU1, #, Guang-hui TU4, Rong-fang HE5, Jin-feng LI1, Di XIE1, 2, Qing-jun GUI2, Yu-chang FU6, Zhi-sheng JIANG1, Jian TU7, *, Chao-ke TANG1, *
1Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang 421001, China; 2Department of Diagnostics, the Medical College, University of South China, Hengyang 421001, China; 3Department of Intensive Care Unit, the First Affiliated Hospital of University of South China, Hengyang 421001, China; 4Department of Pathology, Nan Xian Peoples Hospital, Yiyang 413200, China; 5Department of Pathology, the First Affiliated Hospital, University of South China, Hengyang 421001, China; 6Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA; 7Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China
Aim: To investigate the effects of the major component of high-density lipoprotein apolipoprotein A-I (apoA-I) on the development of atherosclerosis in LPS-challenged ApoE–/– mice and the underlying mechanisms.
Methods: Male ApoE-KO mice were daily injected with LPS (25 μg, sc) or PBS for 4 weeks. The LPS-challenged mice were intravenously injected with rAAV-apoA-I-GFP or rAAV-GFP. After the animals were killed, blood, livers and aortas were collected for biochemical and histological analyses. For ex vivo experiments, the abdominal cavity macrophages were harvested from each treatment group of mice, and cultured with autologous serum, then treated with LPS.
Results: Chronic administration of LPS in ApoE–/– mice significantly increased the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1), increased infiltration of inflammatory cells, and enhanced the development of atherosclerosis. In LPS-challenged mice injected with rAAV-apoA-I-GFP, viral particles and human apoA-I were detected in the livers, total plasma human apoA-I levels were grammatically increased; HDL-cholesterol level was significantly increased, TG and TC were slightly increased. Furthermore, overexpression of apoA-I significantly suppressed the expression of proinflammatory cytokines, reduced the infiltration of inflammatory cells, and decreased the extent of atherosclerotic lesions. Moreover, overexpression of apoA-I significantly increased the expression of the cytokine mRNA-destabilizing protein tristetraprolin (TTP), and phosphorylation of JAK2 and STAT3 in aortas. In ex vivo mouse macrophages, the serum from mice overexpressing apoA-I significantly increased the expression of TTP, accompanied by accelerated decay of mRNAs of the inflammatory cytokines.
Conclusion: ApoA-I potently suppresses LPS-induced atherosclerosis by inhibiting the inflammatory response possibly via activation of STAT3 and upregulation of TTP.
Keywords: apolipoprotein A-I; heart; atherosclerosis; inflammation; cytokines; JAK2/STAT3 signaling pathway; tristetraprolin; lipopolysaccharide; ApoE–/– mice; macrophage
The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (81070220, 81170278, and 81100213), the Heng Yang Joint Funds of Hunan Provincial Natural Sciences Foundation of China (10JJ9019), the Hunan Provincial Natural Sciences Foundation of China (06jj5058), the Science & Technology Department Funds of Heng Yang of Hunan Province (2010kj17 and 2010kj41), and the Hunan Provincial Postgraduate Innovation Fund (CX2010B379).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail tchaoke@yahoo.com.cn (Chao-ke TANG); tujian0734@yahoo.com.cn (Jian TU)
Received 2012-10-11 Accepted 2013-01-19
Keywords:
1Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang 421001, China; 2Department of Diagnostics, the Medical College, University of South China, Hengyang 421001, China; 3Department of Intensive Care Unit, the First Affiliated Hospital of University of South China, Hengyang 421001, China; 4Department of Pathology, Nan Xian Peoples Hospital, Yiyang 413200, China; 5Department of Pathology, the First Affiliated Hospital, University of South China, Hengyang 421001, China; 6Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA; 7Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China
Aim: To investigate the effects of the major component of high-density lipoprotein apolipoprotein A-I (apoA-I) on the development of atherosclerosis in LPS-challenged ApoE–/– mice and the underlying mechanisms.
Methods: Male ApoE-KO mice were daily injected with LPS (25 μg, sc) or PBS for 4 weeks. The LPS-challenged mice were intravenously injected with rAAV-apoA-I-GFP or rAAV-GFP. After the animals were killed, blood, livers and aortas were collected for biochemical and histological analyses. For ex vivo experiments, the abdominal cavity macrophages were harvested from each treatment group of mice, and cultured with autologous serum, then treated with LPS.
Results: Chronic administration of LPS in ApoE–/– mice significantly increased the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1), increased infiltration of inflammatory cells, and enhanced the development of atherosclerosis. In LPS-challenged mice injected with rAAV-apoA-I-GFP, viral particles and human apoA-I were detected in the livers, total plasma human apoA-I levels were grammatically increased; HDL-cholesterol level was significantly increased, TG and TC were slightly increased. Furthermore, overexpression of apoA-I significantly suppressed the expression of proinflammatory cytokines, reduced the infiltration of inflammatory cells, and decreased the extent of atherosclerotic lesions. Moreover, overexpression of apoA-I significantly increased the expression of the cytokine mRNA-destabilizing protein tristetraprolin (TTP), and phosphorylation of JAK2 and STAT3 in aortas. In ex vivo mouse macrophages, the serum from mice overexpressing apoA-I significantly increased the expression of TTP, accompanied by accelerated decay of mRNAs of the inflammatory cytokines.
Conclusion: ApoA-I potently suppresses LPS-induced atherosclerosis by inhibiting the inflammatory response possibly via activation of STAT3 and upregulation of TTP.
Keywords: apolipoprotein A-I; heart; atherosclerosis; inflammation; cytokines; JAK2/STAT3 signaling pathway; tristetraprolin; lipopolysaccharide; ApoE–/– mice; macrophage
The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (81070220, 81170278, and 81100213), the Heng Yang Joint Funds of Hunan Provincial Natural Sciences Foundation of China (10JJ9019), the Hunan Provincial Natural Sciences Foundation of China (06jj5058), the Science & Technology Department Funds of Heng Yang of Hunan Province (2010kj17 and 2010kj41), and the Hunan Provincial Postgraduate Innovation Fund (CX2010B379).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail tchaoke@yahoo.com.cn (Chao-ke TANG); tujian0734@yahoo.com.cn (Jian TU)
Received 2012-10-11 Accepted 2013-01-19